KR101021203B1 - Disposable bioreactor systems and methods - Google Patents

Abstract

According to one embodiment of the invention, a disposable container for containing a biomaterial to be treated, and having at least one inlet port and at least one outlet port; At least one harvest port; A support structure for supporting said disposable container; One or more sensors sensing one or more parameters of the biomaterial in the disposable container; A heating device for heating the contents of the disposable container and having a thermostat; A bioreactor system is provided that includes a mixing system disposed with a bioreactor system to mix biomaterials contained within the disposable container.

Description

Disposable Bioreactor Device and Method {DISPOSABLE BIOREACTOR SYSTEMS AND METHODS}

Embodiments of the present invention relate to methods and apparatus for treating biological materials, and more particularly, to disposable components / apparatus for treating biological materials.

Conventional bioreactors are designed as fixed pressurized vessels in which mixing can be effected by several alternative means, while current disposable bioreactors are devices utilizing plastic sterilization bags. Each bioreactor is used to process biological material (eg, to cultivate plant cells, animal cells). Examples of such treatments include mammalian cells, plant cells or insect cells, and microbial cultures. Such devices can also be used in sterile mixing and non-sterile mixing applications.

Although mixing is performed in a pressurized container using an impeller apparatus, in a disposable bioreactor, mixing was performed by rocking the container before and after the bioreactor. For example, as disclosed in Singh's US Pat. No. 6,544,788, disposable bioreactors have been disclosed in which the disposable bioreactor is mixed by such back and forth motion / process. Such a process cannot be used in a limited, fast and efficient manner. Specifically, the rocking motion is limited to a small number of back and forth motions so as not to stress the encyclopedia system.

In addition, current disposable bioreactors do not comprise a disposable system as a whole, ie probes, sensors and other components generally need to be reused and need to be sterilized before repeated use. Thus, the current state of the art disposable bioreactor systems is not particularly effective when performing the mixing step and delays between use so that probes, sensors and / or other components can be sterilized each time they are used. time)

There is a need for a cost-effective disposable bioreactor system that includes many components for single use, limits downtime between uses, and / or includes an improved mixing system.

Accordingly, embodiments of the present invention address the shortcomings and disadvantages of prior art bioreactor systems and provide an improved disposable bioreactor system. In particular, embodiments of the present invention provide control of mixing, aeration and / or process, and can eliminate the substantial number (eg, most) of conventional auxiliary equipment required to operate the bioreactor.

To this end, some embodiments of the present invention provide a bio-based bioreactor that is based on a disposable bioprocess bag in which a sterile envelope defined by the interior of the disposable bioreactor bag is provided with a disposable component of the mixing system. It includes a reactor system, which does not require the need to swing the envelope or the use of a peristaltic pump for piping outside the bag. In addition, some embodiments of the invention provide a disposable solution as a whole, ie all contact surfaces, including probes and sensors, may be disposable.

These and other embodiments of the present invention have the advantage of reducing the wear and tear of sterile envelopes provided by disposable bioreactors, thereby reducing the likelihood of rupture of sterile envelopes due to mechanical stress. Have Embodiments of the present invention that do not require mixing by oscillating motion also have advantages in non-sterile applications where the integrity of disposable plastic containers is considered important.

Thus, according to one embodiment of the invention, a disposable container for containing a biomaterial to be treated, and having at least one inlet port and at least one outlet port; At least one harvest port; A support structure for supporting said disposable container; One or more sensors sensing one or more parameters of the biomaterial in the disposable container; A heating device for heating the contents of the disposable container and having a thermostat; A bioreactor system is provided that includes a mixing system disposed with a bioreactor system to mix biomaterials contained within the disposable container.

According to another embodiment of the present invention, there is provided a bioreactor system that can include at least one, preferably both, of a support structure and a flexible plastic bag positioned within the support structure. The disposable container may have an impeller plate mounted underneath the plastic flexible bag, which may have a post. The disposable container may also include an impeller hub mounted to the post, the impeller hub having at least one impeller blade and at least one magnet disposed on the post. The bioreactor system may further include a motor provided adjacent to or within the support structure and having a shaft and a motor hub mounted to the shaft of the motor. The motor hub may have at least one magnet, and when the flexible plastic bag is mounted in the support structure, the motor hub may have a magnet of the motor hub to drive the impeller hub when the shaft of the motor rotates. It is aligned with the impeller plate so that it can be aligned with the magnet of the impeller hub.

According to another embodiment of the present invention, there is provided a bioreactor system that can include a support structure, a flexible plastic bag positioned within the support structure. The disposable container includes an impeller plate mounted to the bottom of the flexible plastic bag, a first shaft with a first end positioned inside the flexible plastic bag and a second end positioned outside the flexible plastic bag, surrounding the shaft. And an impeller hub mounted to the first end of the shaft, the impeller hub having at least one impeller blade disposed on the shaft. The bioreactor system can also include a motor disposed adjacent to or within the support structure, wherein when mounting the flexible plastic bag into the support structure, the second end of the shaft is driven by the motor.

These and other objects, advantages and features of the present invention will become more apparent with reference to the following detailed description and accompanying drawings.

Figure 1a is a block diagram of a bioreactor system according to an embodiment of the present invention,

1B is a schematic diagram of a bioreactor system according to an embodiment of the present invention,

2 is a schematic diagram of a disposable bioreactor bag according to an embodiment of the present invention,

3 is a schematic diagram of a mixing system for a bioreactor system according to an embodiment of the present invention,

4 is a schematic diagram of a mixing system for a bioreactor system according to another embodiment of the present invention,

5A is a side view of the impeller hub showing the position of the deformable impeller blade when the impeller hub is at rest, in accordance with an embodiment of the present invention;

FIG. 5B is a side view of the impeller hub according to the embodiment shown in FIG. 5A, illustrating the position of the deformable impeller blade when the impeller hub rotates at a particular speed, and FIG.

6 is a side view of an impeller hub having an impeller blade pivotally fixed according to another embodiment of the present invention,

7 is a view showing three concepts of the bubble column / air-lift mixer applied to the disposable bioreactor according to an embodiment of the present invention,

8A is a perspective view of a support structure / tank having one or more baffles, wherein a disposable bioreactor bag disposed within such a tank is fitted to the baffle,

FIG. 8B is a schematic diagram illustrating an embodiment of the present invention having an air bubble / air-lift mixing system (FIG. 7) and an internal baffle of support structure (FIG. 8A).

A bio-process container forms the material contact surface for the bioreactor. Such a container is preferably a flexible bag that can be placed in a rigid structure, such as a support tank shell. The support structure may also have a movable dolly so that the bioreactor system can move to various positions before, during, or after material processing.

To enable the functions required for the bioreactor, the bag has fittings such as penetrations and filters to allow fluid and gas transport, and a spacing surface to control the mixing interface, sensors and bubble size. This is provided. For use as a bioreactor, the container (including the central bioprocess bag and all deposits, infiltrations, sensors, etc.) can be sterilized (eg gamma irradiation). After sterilization, the inside, tubing, and components of the bag can be considered sterilized to provide a "sterilized envelope" that protects the contents of the container from external contaminants. The size and distribution of the bubbles can be controlled by passing the inlet gas stream through the porous surface before adding it to the interior of the disposable bioreactor. The sparging surface can also be pressurized and depressurized (or vacuum applied) by alternating the outer surface of the porous surface or by inducing decompression along the other part of the surface by high velocity flow along one part of the porous surface (e.g. air in the center of the tube). It can be used as a cell separation device, for example by the Bernoulli effect, which occurs by flowing at high speed in a stream, exiting one end of the tube, and generating a vacuum along the length of the tube).

As shown in FIGS. 1A and 1B, the bioreactor system 100 may include one or more of a disposable bioreactor 102, a temperature controller 106, and one or more sensors and / or probes 108. have. Closed loop water jacket, or electric heating blanket 104, heated and / or cooled by a control system mounted on the bioreactor, to remove the necessary equipment for temperature control through the heat exchanger. Heating may be provided by a blanket or by a Peltier heater. The heating blanket may have a thermocouple 104a for sensing the temperature of the contents of the bioreactor 102, which thermocouple operates in conjunction with a temperature controller to control the set temperature of the contents of the bioreactor 102. . If desired, a temperature conducting material may be embedded in the surface of the bag to overcome the insulating effect of the plastic.

According to some embodiments of the invention, the disposable bioreactor may comprise a plastic flexible bag and may also include a rigid material (eg, plastic, metal, glass). The sensor and / or probe is connected to a sensor device 132, the output of which is sent to either or both of a terminal plate and a relay. A mixing system 110 may also be provided having a motor 112, a power regulator 114, and a motor controller 116 that generally drive an impeller positioned in the bioreactor.

In addition, cooling can be provided by a closed loop water jacket that is heated and / or cooled by a control system mounted on the bioreactor or by standard heat exchange through a cover / jacket on the tank (heating blanket for heating / cooling). May be included in the device, or may be separate from the cooling jacket). Cooling may also be provided by the Peltier cooling unit. For example, a Peltier cooling device can be applied to a discharge line (eg, a small bag-like chamber with a large volume and a large surface area to slow down the air) to condense the gas in the exhaust air to prevent the exhaust filter from getting wet.

Air (compressed or pumped) air, oxygen and / or CO ₂ gas 118 may be provided to spray the contents of the bioreactor. Filter 120, flow meter 121 and / or valve 122 (such as a pneumatic valve) may be provided in-line, where the valve is provided to controller system 115, which may be a PC as shown. Can be controlled. Such controller systems can include a combination of electrical systems, mechanical systems, and pneumatic systems to control air, liquid, and heat into a disposable bioreactor system. As shown in FIGS. 1A and 1B, the valve 122 may be a pneumatic actuator (eg, using compressed air / CO ₂ 124) that may be controlled by the solenoid valve 126. The solenoid valve may be controlled by a relay 128 connected to the terminal plate 130 connected to the PC. The terminal block may include a PCI terminal board, a USB / parallel, or a FireWire (IEEE 394) terminal board connection.

As shown in FIG. 1B, the disposable bioreactor is preferably supported by a support structure 101, which is shown as a tank (eg, stainless steel) mounted on top of the base 103. And a plurality of legs 105. The tank may be designed to have a height and diameter similar to standard stainless steel bioreactors. Such a structure may be scaled down to a small bench bioreactor volume, and may (eg) extend beyond an operating volume of 1000L. A baffle 800 (see FIGS. 8A and 8B) can be installed inside the rigid tank shell 802 to facilitate mixing by conforming the bag to the shape projecting into the bioreactor bag, which preferably disrupts circulating flow. And / or prevent (eg) swirling.

At least one of the legs (preferably all legs) may be a load cell 107, which load cell may be used to estimate the weight of the contents of the bioreactor and / or the weight of the tank and the corresponding components of the tank. Can be used. The tank may include a viewing window 101a, which allows to view the liquid level in the disposable bioreactor. The viewing window can be sized to view a large area of the bioreactor. The tank may also have a sensor / probe port 101b and an outlet 101c, to which an outlet pipe 101d may be connected. At the top of the tank, one or more connections 101e (e.g., tubes, valves, openings) are provided for adding fluids, gases, etc. to the bioreactor or withdrawing (e.g. inhaling / exhausting) from the bioreactor, each of which is It may include a flow sensor 101f and / or a filter 101g. A utility tower (101h) may be provided on or adjacent to the tank, which tower houses one or more pumps, controllers and electronics (sensor devices, electronics interfaces, pressurized gas controllers, etc.). Can be used.

Sensors / probes and controls monitor and control critical process parameters, including (eg) any one or more of temperature, pressure, pH, dissolved oxygen (DO), dissolved carbon dioxide (pCO ₂ ), mixing rate, gas flow rate. Or combinations thereof. Desirable process control can be achieved in a manner that does not compromise the sterile barrier established by the bioreactor. In particular, the gas flow rate can be monitored and / or controlled by a rotameter or mass flow meter upstream of the inlet air filter.

Disposable optical probes can be designed to take advantage of a "patch" of material containing an indicator dye, which is mounted on the inner surface of the disposable bioreactor bag so that it can Can be read through the wall. For example, optical patches and sensors mounted on biocompatible polymers capable of irradiating gamma rays can monitor and control dissolved oxygen (DO) and / or pH and / or CO _2, respectively, and the polymer is directed to the surface of the bag. It may be sealed, embedded therein, or otherwise attached.

Pressure can be monitored and controlled by standard pressure transducers upstream of the inlet air filter and downstream of the outlet air filter. Alternatively, the sterilized envelope of the disposable bioreactor by lifting a shelf device (eg, available from Utah Medical or Honeywell) or by forming a tee in the air inlet and / or outlet lines. A disposable pressure sensor can be used inside. The surface of the tee may be covered with a thin film to maintain a sterile barrier, but should be made so as not to affect the pressure reading. A standard pressure transducer can then be installed on the tee to measure and control the pressure inside the sterilization barrier.

2 illustrates an example of a disposable bioreactor 200 in accordance with some embodiments of the present invention. As shown, the bioreactor includes one or more ports 202, which can be used to add and withdraw gas and / or fluid into and out of the bioreactor. Since a collection or discharge port 204 is generally provided at the bottom of the bag, gravity can be used to direct the contents out of the bioreactor. The probe and / or sensor 206 may be integral to the side of the bioreactor, and the sensor and / or probe may likewise be disposable. According to one embodiment of the invention, the sensor / probe may be an optical probe that visually represents the output. Thus, sensor / probe port 101b can be used to visually monitor the state of the sensor / probe.

One part of the mixing system may be integrated with the bioreactor. Specifically, as shown in FIG. 2, the portion of the mixing system provided with the bioreactor may include one portion 208 of the mixing system, namely the impeller plate and the impeller hub. The impeller plate is connected to a drive system of the motor that powers the impeller and also provides a seal between the motor and the interior of the bioreactor.

Some embodiments of the present invention provide one or more special mixing systems, thereby providing a method of stirring the contents of the bioreactor at low cost in the bioreactor system. Such mixing systems may use materials such as HDPE (High-density polyethelene) and / or other biocompatible plastics capable of irradiating other gamma rays. One or more components of the mixing system may be manufactured by machining a block of material, and may be molded and / or cast.

An embodiment of such a mixing system is shown in FIG. 3. The mixing system according to this embodiment provides a magnetically driven impeller so that the motor is not directly connected to the impeller. Instead, the magnet housed in the motor hub drives the magnet housed in the impeller hub by magnetic attraction. It is worthwhile to be able to mount at least the motor part (and other motor related parts) to the support structure / tank / dolly.

As shown, the system generally includes an impeller plate 300, an impeller hub 304, a motor 306, a motor shaft 308, and a motor hub, which are generally mounted on the sides, preferably the bottom, of the bioreactor wall 302. 310. The impeller plate may be mounted to the wall of the bioreactor by heating and welding two halves of the two part impeller plate together and sandwiching the wall of the bioreactor between them, or by welding the two halves to the bioreactor wall. Alternatively, due to the opening in the wall of the bioreactor, the central portion of the impeller plate may extend from the outside of the bioreactor to the inside or vice versa. Thereafter, a sealing ring (not shown) may be attached to the outer periphery of the impeller plate to seal the wall of the bioreactor between the impeller plates, and the bioreactor wall may be heated and welded to the outer periphery. Another alternative is to have a small opening in the wall of the bioreactor form a seal with the circumferential edge of the impeller plate slightly larger than this opening.

One important feature according to one embodiment of the invention relates to the employment of one or more porous elements or ultrafiltration elements 301 in the impeller plate. This element can be used to spread gas or fluid into and out of the bioreactor. Such fluid sparging and / or addition or removal may be used in connection with the mixing system (ie rotation of the impeller hub). This sparging uses a mixing force (usually air) near the bottom of the reactor. The rising gas becomes bubbles, the low density gas saturated liquid rises, and the gas lean liquid falls and provides a top to bottom circulation. The path of the rising liquid can be guided by a divider inside the chamber of the bag or via a baffle (see above). For example, such a bag may comprise a plastic sheet that bisects the chamber of the bag vertically at intervals at the top and bottom. Since gas can be added only to one side of the divider, the gas and gas rich liquid rises across the top of the barrier on one side and descends to pass under the divider on the other side to return to the gas addition point.

According to some embodiments of the present invention, a high shear zone under the rotating impeller can increase the performance characteristics of the system. When used with the porous material described above (having macro, micron, submicron or nano pore sizes), the shear zones serve a variety of purposes: gas sparging, fluid withdrawal from the vessel, Solid / liquid or cell culture separation (eg, any particulate separation that maintains the solid in the bioreactor and removes the fluid filtrate) and the like, and the like, such as semi-perfusion culture or continuous perfusion culture, cell separation, resin Separation, etc., and the concentration or buffer of the product or solute is exchanged in applications where the porous element is in the ultrafiltration range.

According to the embodiment shown in FIG. 3, the inner side of the impeller plate may include a post 312, which is received in the central opening of the impeller hub 304. The impeller hub is preferably held at some distance above the surface of the impeller plate to prevent friction between them. Low friction materials can be used to fabricate the impeller hub to minimize friction between the impeller hub and the post. Alternatively, bearing 311 may be provided to reduce friction.

The impeller hub preferably comprises at least one magnet 314 and preferably comprises a plurality of magnets, which magnets are positioned around the hub and are preferably provided in the motor hub 310. Corresponds to the position of 316. The impeller hub also has one or more, preferably a plurality of impeller blades 318. It is worthwhile that a magnet embedded in the impeller can remove iron particles or magnetic particles from a solution, slurry or powder.

Motor hub 310 is generally mounted in the center of shaft 308 of motor 306. In addition to the magnet 316, the motor hub may also include a lazy-susan bearing (322) to prevent friction between the motor hub and the impeller plate, but alternatively a low friction material to reduce friction. (Such as low friction plastic) may be used.

Lazy Susan bearings also contribute to minimizing the gap between the motor hub and the impeller plate. It is desirable for the impeller plate to have a thickness as thin as possible, but often cannot be achieved. As the size of the tank increases, the hydrostatic pressure inside the tank and the impeller plate increases, resulting in downward deflection / deformation of the impeller plate and the central post. If the deformation is not prevented, the impeller hub can reach on the impeller plate, causing drag, thereby reducing the engagement force and causing friction. As a result, particles can be diverted into the contents of the bioreactor. The lazy-susan bearing mounted at the center of the motor hub can thus support the lower surface of the impeller plate to help prevent deflection of the impeller plate due to hydrostatic pressure. This feature thus ensures proper operation of the impeller in large applications and allows the use of very thin impeller plates while maximizing torque transmission.

Applicants of the present application have found that the torque strength transmitted from the motor hub to the impeller hub via magnetic coupling can be determined by one or more of the following. That is, the width of the gap between two hubs collectively including the width of the impeller plate and the sum of the gap between the impeller hub and the plate and the gap between the motor hub and the plate; Avoiding or removing any hindered iron or magnetic material in the motor hub, impeller plate or impeller hub (in some embodiments of the invention, this is achieved by, for example, manufacturing some or all components of the mixing system from plastic ); Number of magnets; Magnetic force of the magnet; Number of concentric magnetic rings; Distance from the center of the hub to the magnet.

Thus, the spacing between the two hubs may be adjusted preferably between about 0.001 inches and 0.750 inches, more preferably between about 0.125 inches and about 0.500 inches. The number of magnets used may be one, but preferably about 2 to 50, most preferably about 3 to 10, such magnets are about 1 to 100 million Gauss Oersted (MGOe), most preferably Has a magnetic force of about 20 to 50 MGOe. According to one embodiment, the type of magnet used is a grade of neodymium magnet. Preferably the grade of neodymium is N38, which has a maximum energy product of 38 MGOe. The number of concentric magnet rings can be from one to four, with the distance from the hub of the magnet ring from about 0.250 inches to about 16 inches, most preferably from about 0.500 inches to 12 inches.

4 shows a variant of the mixing system in connection with a mechanically driven impeller. As shown, this embodiment generally includes an impeller plate 400, an impeller hub 404 with a shaft 405, and an external motor 406 with a shaft 408. The shaft connection between the shaft of the impeller hub and the shaft of the external motor can be achieved in a manner known to those skilled in the art (eg gearbox, hex drive, etc.).

The impeller plate is preferably attached to the side of the bioreactor at the bottom thereof. The impeller plate may be attached to the wall of the bioreactor by any of the methods mentioned in connection with the embodiment of FIG. 3. A porous, micro-porous, or ultrafiltration element 401 may be provided in this embodiment to spread gas or fluid into and out of the bioreactor.

In the embodiment shown in FIG. 4, the shaft of the impeller hub may be received in a seal 412 (which may also include a bearing) located at the center of the impeller plate. The seal ensures that the contents of the bioreactor are contaminated. The impeller hub is preferably held at some distance above the surface of the impeller plate to prevent friction between them. The impeller hub also has one or more, preferably a plurality of impeller blades 418.

In another embodiment (see FIGS. 7 and 8B), a bubble column or airlift system (which utilizes the bubbles of air / gas 701) is used with a disposable bioreactor bag, which is a gas near the bottom of the reactor. (Eg, air) to provide mixing power. Such an implementation may include a bubble column 700, an airlift fermenter 702 with an internal draft tube 703 and an airlift fermenter 704 with an external draft tube 705 (bubble direction). May correspond to the direction of the arrow).

The rising gas thus becomes bubbles, the low density gas saturated liquid rises, and the gas lean liquid falls and provides a top to bottom circulation. The path of the ascending liquid can be guided by a divider inside the chamber of the bag. For example, such a bag may use a plastic sheet that bisects the interior of the bioreactor bag vertically at intervals at the top and bottom. As gas may be added to one side of the divider, the gas and gas rich liquid rises across the top of the barrier on one side and descends to pass under the divider on the other side to return to the gas addition point. It is worthwhile to be able to combine the bubble column / air-lift system and method with any of the impeller based mixing systems described above.

For any impeller-type mixing system, further embodiments may relate to impeller blades of variable pitch. As shown in Figures 5 and 6, the variable pitch blades may include pivotable deformable blades or impeller blades. Specifically, as shown in FIG. 5A, the impeller hub 500 may have a variable pitch blade 502 that is deformable, which blade may be mounted when the impeller hub is stationary (or the top surface of the impeller hub and / or Or at a small angle 503 with respect to the bottom surface] in a substantially reclining position and inclined at an angle 504 with respect to the top and / or bottom surface of the impeller hub as the impeller hub rotates. The angle of the blade forming with the impeller hub may depend on the rotational speed of the impeller hub, so that as the impeller rotates at a higher speed, the blade is more inclined with respect to the top and / or bottom surface of the impeller blade. The materials used in the fabrication of the impeller blades with flexibility can be used to provide the functions described above (according to one embodiment of the present invention). Such flexible materials (eg plastics, engineering plastics) are known to those skilled in the art.

According to the variant shown in FIG. 6, the pitch of the impeller blades 602 relative to the top and / or bottom surface of the impeller hub 600 can be obtained by manually rotating the blade relative to the impeller hub. This can be accomplished by fabricating an impeller hub having respective openings to receive the pivot shafts of each blade. The shaft may be slightly larger than the size of each opening in the impeller hub. Alternatively, an impeller hub having a predetermined predetermined blade pitch may be manufactured and provided inside the bioreactor. Thus, bioreactor bags with specific set pitches can be fabricated individually and usefully used in specific applications.

The mixing system described above allows the system to mix any type of fluid or solid. In particular, the fluid inside the bioreactor may be mixed to provide a distribution of nutrients and degraded gases for cell growth applications. The same disposable container can be used to mix buffers and media or other solutions, where disposable product contact surfaces are advantageous. The system of the present invention also includes applications where there is no need to sterilize the container or maintain the sterilization of the container. In addition, the system of the present invention enables the removal and disposal of tanks containing fluids / mixtures / gases in such a way that the tanks are not contaminated by the fluids mixed in the bioreactor bag. Thus, the tank does not need to be cleaned or sterilized at every use.

Yes

Testing was performed by mixing water with a CHO (mammal) cell expressing a 150 L scale antibody fusion protein using a self-driven HDPE impeller, a mixing HDPE plate and shaft, and a porous HDPE tubing for sparging. Optical patches for DO provided dissolved oxygen monitoring and feedback control of gas flow. The temperature on the outer surface of the bag was controlled by the thermocouple and the heating blanket was provided on / off by the electrical blanket. In this test run, mammalian cells grew at high density and maintained at high viability, demonstrating successful susceptible reduction to realize this structure for cell culture.

Example 2-List of Components of a Disposable Bioreactor System

The following is a list of components for an exemplary bioreactor system having a disposable bioreactor bag (see also FIG. 1B) in accordance with an embodiment of the present invention.

Subassembly Component QTY Description / Options

Components Quantity Explanation Tank shell of tank One 316SS tank shell equipped Coils and insulators in tanks One Heat transfer path around the tank shell Temperature control unit One Self-contained TCU integrated into the main skid controller Jacket hose of tank One Connection between TCU and Tank Coil Sight glass of tank One Field of view window on the side of the tank cell Plumbing manager One Panel with piping grommet on top of tank I & C pH Probes and Analyzers 2 Dissolved oxygen and analyzer 2 Load cell 3 Load cell analyzer One Thermocouple 5 Flow Meter-Spray One Rotameters with local visual indication of flow to the spreading element Flow Meters-Head Sweep One Rotameters with local visual representation of flow to headspace Flow switch-discharge line One Flow detector indicating filter flow or blockage Mass Flow Controller-Head Sweep One Mass Flow Controllers-Spreader 4 Acid feed pump One Peristaltic Pump-Small Basic feed pump One Peristaltic Pump-Small Semi-Formular Feed Pump One Peristaltic Pump-Small Medium feed pump One Peristaltic pump Discharge pump One Peristaltic pump Stirrer motor, reducer,
Drive head One Stirrer Controller One Shoulder 1/2 HP Washdown Duty or Equivalent Power splitter One Belt washdown duty or equivalent I / O Cabinets and Switches One PLC controller One Operator interface

While some embodiments of the invention have been described above, the foregoing is illustrative only and is provided by way of example and not by way of limitation. Numerous variations and other embodiments, which will be appreciated by those skilled in the art, are considered to be within the scope of the invention as defined by the appended claims and their equivalents.

Claims (29)

As a bioreactor device, A disposable container for containing a biomaterial to be treated and including a flexible plastic bag having at least one inlet port, A plurality of fittings added to the flexible plastic bag to enable the functions required for the bioreactor, with infiltration and filters allowing fluid and gas transport, mixing interfaces, sensors, and spraying to control bubble size A plurality of fittings comprising surfaces; An impeller plate mounted to the bottom of the flexible plastic bag, the inner side of the impeller plate comprising a post and the impeller plate further comprising at least one porous or microporous element capable of allowing gas sparging into and out of the bioreactor. With impeller plate, A disposable mixing device having an impeller comprising an impeller hub mounted on the post and maintained at a distance above the surface of the impeller plate, the impeller hub having at least one impeller blade and at least one magnet, the impeller A disposable mixing device configured to be driven by a motor outside the disposable container and magnetically connected to the motor to mix the biomaterial contained in the flexible plastic bag and increase gas bubble circulation; At least one outlet port, At least one harvest port, A support structure for supporting the disposable container; At least one sensor for sensing at least one parameter of the biomaterial in the disposable container, Heating device for heating the contents of the disposable container and having a thermostat Bioreactor device comprising a. delete The bioreactor device of claim 1, wherein the disposable container includes one or more baffles configured to limit circulating flow or prevent vortexing. The bioreactor device of claim 1, wherein the disposable mixing device comprises a bubble column associated with a partial divider positioned within the disposable container. The bioreactor device of claim 1, wherein the porous surface is disposed to allow unidirectional or bidirectional fluid communication between the interior of the disposable container and the exterior of the disposable container. The bioreactor device of claim 1, wherein the heating device comprises an electric heating blanket or Peltier heater disposed outside of the disposable container. The bioreactor device of claim 1, wherein the heating device comprises a closed loop water jacket that is heated, cooled, or heated and cooled by a control device mounted to the bioreactor. 8. The bioreactor device of claim 7, wherein the heating device is positioned inside or outside the disposable container. The bioreactor device of claim 1, wherein the one or more sensors include a sensor that senses at least one of dissolved oxygen, dissolved carbon dioxide, mixing rate, gas flow rate, temperature, pH, and pressure. The bioreactor device of claim 1, further comprising a computer controlling the bioreactor device. The bioreactor device of claim 1, further comprising at least one of an air supply, a carbon dioxide supply, and an oxygen supply. The bioreactor device of claim 1, further comprising a conveying means for moving the support structure. 13. The bioreactor device of claim 12, wherein the conveying means comprises a dolly. As a bioreactor device, Support structures; A disposable container comprising a flexible plastic bag positioned within the support structure, the flexible plastic bag comprising: An impeller plate mounted to the bottom of the flexible plastic bag, the impeller plate being at least one arranged to allow one-way or two-way fluid communication between the posts on the inside of the impeller plate and the inside of the flexible plastic bag and the outside of the flexible plastic bag An impeller plate, wherein the fluid communication is configured to introduce gas sparging into the disposable container or to remove fluid from the interior of the disposable container; A disposable impeller hub mounted on the post and held at a distance above the surface of the impeller plate, the disposable impeller blade having at least one disposable impeller blade and at least one magnet, wherein the at least one impeller blade is disposed on the post Disposable impeller hub with A motor provided with or adjacent to the support structure and having a shaft; A motor hub mounted on the shaft of the motor and having at least one magnet And the mounting of the disposable container including the flexible plastic bag in the support structure, wherein the motor hub has a disposable magnet for driving the disposable impeller hub when the shaft of the motor rotates. The bioreactor device being aligned with the impeller plate so as to be aligned with the magnet of the impeller hub. 15. The bioreactor device of claim 14, wherein the motor hub further comprises a lazy-susan bearing, the bearing being positioned within the hub such that a portion of the bearing contacts one side of the impeller plate. delete delete The bioreactor device of claim 14, wherein the at least one disposable impeller blade comprises an impeller blade of variable pitch. 19. The bioreactor device of claim 18, wherein the pitch of the disposable impeller blade is changed in accordance with the rotational speed of the impeller hub. 19. The bioreactor device of claim 18, wherein the pitch of the disposable impeller blade is adjusted manually. delete delete The bioreactor device of claim 1, wherein the porous or microporous element is further adapted for use as a particulate separation device. The bioreactor device of claim 1 or 14, wherein all surfaces configured to contact the biomaterial received for processing are disposable. The bioreactor device of claim 14, wherein the at least one porous element is further adapted for use as a particulate separation device. 15. The bioreactor device of claim 14, wherein the disposable impeller hub and the motor hub each comprise at least two magnets. The bioreactor device of claim 14, wherein all surfaces configured to contact the biomaterial received for processing are disposable. delete delete

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